Heart failure is a deadly disease that affects 5 million Americans. It incurs an estimated annual cost of 38 billion dollars. Despite recent advances, the prognosis remains grave. In heart failure, there is a powerful increase in sympathetic nerve traffic to the heart itself. This response is maladaptive, however, because it promotes disease progression and death. Its causes are inadequately understood. If identified, they could be an excellent target for future therapy. Cardiac sympathetic nerve activity (CSNA) can be studied only indirectly in humans, but direct measurements are now possible in animals. This application uses new techniques to make direct measurements of CSNA in conscious, unstressed sheep, and in sheep with experimental heart failure (pacing model). Studying first the reflex and hormonal factors that determine CSNA in normal animals, the idea will be tested that normal cardiovascular reflexes responding to abnormal hemodynamics can raise CSNA disproportionately compared with other sympathetic outflows. This will be achieved by making simultaneous recordings of CSNA with lumbar sympathetic nerve activity, for comparison. As part of this investigation in normal animals, rapid cardiac pacing will be used to simulate the hemodynamic changes of heart failure, without the chronic features of the established disease. Equivalent experiments will then be performed on animals with heart failure, induced by rapid cardiac pacing for 3-4 weeks. Comparisons with normal animals will show how much CSNA is raised in heart failure, and how much the raised sympathetic drive is selective for the heart. Experiments will then test whether the raised CSNA of heart failure is driven by angiotensin (circulating or in the brain), or by other agents acting on brain circumventricular organs. Finally, parallel measurements of CSNA and cardiac norepinephrine spillover will be made in order to relate these findings to clinical studies. The results will increase understanding of a deadly disease and help guide future approaches to therapy and prevention. [unreadable] [unreadable]